Enema-type laxative composition



United States Patent 3,211,614 ENEMA-TYPE LAXATIVE COMPOSITION Paul Gunnar Embring, Uppsala, and Per Ove Mattsson,

Stockholm, Sweden, assignors to Aktiebolaget Pharmacia, a company of Sweden No Drawing. Filed July 10, 1963, Ser. No. 294,151

6 Claims. (Cl. 16756) This is a continuation-in-part of our application Serial No. 52,866, filed August 30, 1960, now abandoned.

The present invention generally relates to a novel and highly effective laxative composition of that type which is to be administered through the anus. More specifically the present invention pertains to a laxative composition which effects a complete removal of the colon contents without requiring large quantities of Water to be introduced ino the colon and without any risk of the fluid balance of the body being distributed. (For the purpose of this specification and claims the terms laxative composition and enema composition are considered to be substantially synonymous and equivalent.)

BACKGROUND In order to carry out a number of medical investigations it is very important that the colon be emptied as completely as possible. This particularly applies with respect to the visual inspection of the rectum and sigmoideum for diagnostic purposes. It is most important for X-ray investigations of the colon and rectum, in which interpretation of the images obtained is made more difficult, or impossible, by contrast-producing faeces. Other types of X-ray investigations in which the possibilities of interpreting the X-ray images are also decreased due to contrast-producing intestinal contents, are urography, hysterosal-pingography, cholecystography and pelvicarteriography.

The term X-ray investigations is used herein means both those investigations wherein X-rays, after having passsed through different parts of the body, are intercepted a: an image on a photographic plate, and such investigations wherein the passing rays are caused to strike upon a fluorescent surface on so-called irradiation.

In order to effect an emptying of the colon, water enemas have previously been employed wherein large quantities of water, often containing various additives, are introduced into the colon to induce its emptying, the contents of the colon being expelled in the form of a suspension.

However, in the last few years it has been found that the introduction of too large a quantity of water in enemas may be injurious and cases of so-called water poisoning, particularly in the field of child nursing, have been reported in the professional press. (See, for example, Lancet, 1959:1/7072, pages 559560, Hazard of Water Enemas.) It may further be mentioned that in connection with such X-ray investigations of the urinary tract, which are based on the excretion of contrast agents, any supply of water to the body may result in the dilution of the contrast agents, and for this reason the supply of liquids should be as small as possible.

In view of these hazards and disadvantages small enemas of a hypertonic aqueous solution of sodium phosphate are sometimes substituted for the large water enemas, the effect of these small enemas being based on an increase of the crystalloid osmotic pressure in the colon. However, these small enemas may have undesirable side effects if the solution diffuses through the wall of the colon and disturbs the fluid balance of the body.

OBJECTS The main object of the present invention is to provide a laxative composition which is highly effective in the treatment of constipation.

A second object of the invention is to provide a laxative composition to be used as an aid in connection with medical investigations wherein it is important to empty the colon as completely as possible.

A third object of the invention is to provide a laxative composition adapted to be placed in a disposable container holding a quantity of laxative sufficient to effect a complete evacuation of the colon after having been administered through the anus.

These and other objects and advantages will be evident after reading the following description.

THE PRESENT INVENTION In accordance with this invention we have found a therapeutically acceptable laxative which overcomes the disadvantages referred to above and effects a complete removal of the colon contents without requiring large quantities of water to be introduced into the colon and without any risk of the fluid balance of the body being disturbed.

The present invention, in its broadest scope, involves the preparation of laxative compositions containing as its essential active ingredients:

(a) An alkali salt of an aliphatic polybasic organic hydroxy acid selected from the group consisting of citric acid, tartaric acid, malic acid and ascorbic acid; and

(b) A polyhydroxy alcohol having at least five hydroxyl groupsthe hexatols such as mannitol, sorbitol and dulcitol being preferred over the pentitols such as arabitol, xylitol and adonitol.

In principle, the effect of the laxative composition in accordance with the present invention differs from that aimed at in previous enema compositions.

The main purpose of our invention is to form a suspension of the colonic contents in their own water, which is accomplished by causing the laxative composition to penetrate into the colonic contents, which may be considered to be a precipitated swollen organic colloidal substance containing relatively large amounts of water. A peptization of the colloidal substance with the liberation of the water is thereby effected and the resulting smaller particles form a suspension with this water which leaves the colon during the emptying process.

The laxative composition in accordance with our invention may be prepared in the form of a solution or it may be prepared so as to have an ointment-like appearance.

The laxative composition in accordance with our invention has proved to be particularly effective for various types of colonic constipation. By the same method it is also possible to effect a complete emptying of the colon without any injurious effects so that X-ray investigations 3 of the colon and surrounding organs can be carried out without any risks of the presence of confusing contrasts on the X-ray images obtained. In this respect the subject matter of the present invention represents an important advance in the medical diagnostic field.

This type of laxative has also been used in connection with investigations other than X-ray examinations, wherein it is of importance that the colon should be carefully emptied. Thus, the laxative has proved to be a valuable aid for direct studies of the intestinal mucous membrane, for investigations of suspected tumors (biopsies) and for gynaecological examinations.

pH of the laxative composition In order that the laxative composition in accordance with the invention may meet the requirement of being therapeutically acceptable, its pH-value should preferably not be too far away from the neutral point on each side thereof. On the acid side, a lower limit of pH-value 6 is probably preferable, but it should be pointed out that somewhat lower pH-values may be used. However, when using pH-values lower than about 6, it may be necessary to add a local anaesthetic to the laxative composition so that pains shall not occur in the use thereof. As a preferable upper limit on the alkaline side of the neutral point, a pH-val-ue of about 9 can be stated. In fact, it is preferable that a pI-I-value of about 8 should not be exceeded. However, pH-values higher than 9 could be used here and the disadvantages obtained compensated for by incorporating a local anaesthetic in a sufiicient amount to remove the risk of pain occurring when the laxative is used.

OTHER INGREDIENTS Although the essential ingredients of a laxative composition in accordance with this invention have been set forth above, those skilled in the art will readily appreciate that the laxative composition may also include a number of other ingredients to enhance the overall effectiveness of the laxative composition.

Wetting agents.-In the event that the laxative composition has a wetting agent incorporated therein the latter may be of either the anionic, the cationic or the nonionic type. As anionic mention may be made of dioctyl sodium sulfosuccinate, sodium lauryl sulfoacetate, sodium lauryl sulfate, sodium tetnadecyl sulfate. As cationic wetting agents mention may be made of the quaternary ammonium compounds which may be characterized as synthetic salts of organic, nitrogen-containing compounds. Examples of cationic wetting agents are benzalkonium chloride (alkylbenzyldimethylammonium chloride), benzethonium chloride, benzyldimethyl [2- (2-- /1,1,3,3 tetramethylbutylphenoxy/ethoxy)ethyl] ammoniumchlon'de, monohy-drate, cetyl pyridinium chloride (the monohydrate of the quaternary salt of pyridine and cetyl chloride), mefhylbenzethonium chloride, benzyldimethyl [2(2-/1,-1,3,3-tetramethylbutylcresoxy/ethoxy)ethyl] ammonium chloride. As n-onionic Wetting agents mention may be made of esters of polyhydric alcohols and fatty acids, for example, polyoxyethylene sorbitan mono-oleate wetting agents that are marketed under the trade name Tween by the Atlas Powder Company.

Anaesthetics.- Loca'l anaesthetics in an amount within the range of about 0.5- may be suitably incorporated in the laxative composition. As examples thereof should be mentioned butethamine formate (2-isobutylaminoethyl p-aminobenzoate formate), mon-ocaine hydrochloride (2- isobutylaminoethyl p-aminobenzoa-te hydrochloride), nu-

percaine hydrochloride (2butoxy-N-/2-diethylaminoethyl/cinchoninamide), diothane hydrochloride (3-/'1-piperidyl/-1,2-propanedi-ol dicarbanila-te hydrochloride), diothane (3-/ l-piperidyl/ -l,'2-propanedio1 dicarbanilate), xylocaine hydrochloride (alpha-diethylamino-2,6-|acetoxylidide hydrochloride) amylsine hydrochloride (Z-amylaminoethyl p aminobenzoate hydrochloride), metyc-aine hydrochloride (3-/2-methyll-piperidyl/propyl :benzoate hydrochloride) pH stabilizers.Minor amounts of substances capable of stabilizing the pH of the laxative composition within the desired pH limits of 6 and 9 may be added. As examples of agents capable of stabilizing the pH in the pH range 7-9 mention may be made of 3-(trishydr-oxymethyl) aminomethane, N-dimethylleucylblycine, diethanolamine, triethanolamine. As examples of agents capable of stabilizing the pH in the 'nange.67 mention should be made of glycocoll, glycine, sodium bicarbonate, mixtures of sodium monophosphate and sodium diphosphate, borax. (See: Bates, Electrometric pH determinations, Theory and practice, 1954, pages 114-116). The content of the pH-stabilizing agent may amount to 10 percent, and does not usually exceed about 5 percent.

Glycerol.We have found that it is usually desirable to include glycerol in our laxative compositions in order to promote the solubility of the components of the laxative, particularly when the latter contains a wetting agent.

Viscosity increasing agen t.The laxative compositions may also contain a viscosity increasing agent such as polysaccharides, for example, dextr-an, insulin, water soluble starch, pectin, gummi arabicum, carboxymethyl compounds of starch and cellulose; polypeptides and proteids, for example, gelatin; synthetic polymers, for example, polyvinylpyrrolidone. The content of the viscosity increasing agent may amo-unt to about 10 percent but does preferably not exceed about 5 percent.

AMOUNTS OF LAXATIVE COMPONENTS The percentages of the different ingredients of the laxative compositions in accordance with the invention may vary within the limits evident from the following table:

Percent Alkali salt of hydroxy acid 2 15 An .alcohol having at least five hydroxy} groups :10-80 Water 5-70 Glycerol 0-15 Wetting agent 0-5 The effect of the glycerol begins at the limit 0.02 percent and that of the wetting agent at 0.01 percent. At 0.2 percent the effect of the glycerin is still more remarkable.

Preferable limits with respect to the percentages are set forth in the following table:

Percent Alkali salt of hydroxy acid 4-10 An alcohol having at least five hydroxy groups 20-65 Water 8-40 Glycerol 00 2- 12 Wetting agent 0.01-3

Preferably the laxative compositions referred to contain the different ingredients listed in the .tables in a total amount of at least percent, and most preferably at least '95 percent.

Additional substances may be present in percentages preferably amounting to not more than 10 percent and most preferably not more than 5 percent.

EXAMPLE S The following examples are illustrative of preferred embodiments of the present invention. It should be understood that these examples are not intended to limit the invention and that obvious changes may be made by those skilled in the art without changing the essential characteristics and the basic concept of the invention. The parts and percentages are by weight, the temperature is room temperature and the pressure is atmospheric unless otherwise indicated.

EXAMPLE 1 A laxative composition was made up by mixing together the following ingredients:

G. Sodium citrate (three-basic) Sodium lauryl sulfoacetate 2 Glycerol 10 Water 10 Sorbitol (70 percent aqueous solution) to 100 This composition, the pH of which was 7.4, proved to be a particularly effective laxative and as such it was valuable for medical investigations wherein the colon had to be emptied.

The above composition, the pH of which was 7.4, was particularly effective as a laxative and quite suitable for medical investigation, wherein it is of importance that the colon should be carefully emptied. Also, the composition is easily endurable Without pain resulting from its use.

EXAMPLE 3 A laxative composition was made up by mixing the following ingredients:

G. Sodium citrate (three-basic) 50 Dioctyl sodium sulfosuccinate 20 Glycerol 50 Sorbitol (70 percent aqueous solution) to 1000 The solution with a pH-value of 7.2 was placed in disposable containers with 10 ml. in each unit. The quantity in most cases proved to be sufiicient to remove the most severe constipation in the colon and removed the contents of the colon completely so that the organs in the vicinity of the colon could be diagnosed without disturbances due to contrast produced by faces in the colon.

EXAMPLE 4 An effective and useful laxative composition was made up from the following ingredients:

Sodium ascorbate 7.5 Mannitol 25.0 Water, sufficient to make 100 EXAMPLE 5 An effective and useful laxative composition was made up from the following ingredients:

G. Sodium potassium tartrate 9 Polysorbate 20 (Tween 20) 1 Sorbitol 60 Water, sufficient to make 100 EXAMPLE 6 An effective and useful laxative composition was made up from the following ingredients:

Malic acid 6.5 Sodium bicarbonate 4 Benzethonium chloride 0.05 Glycerol 5 Polyalkohol-Mischung PA 70 (viscous aqueous solution of sorbitol and xylitol) sufficient to make 100 6 EXAMPLE 7 Sodium lauryl sulfoacetate 64.8% active by weight 1.09 Sorbic acid 0.078 Glycerol 9.77 Sodium citrate 7.03 Sorbitol (70% aqueous byweight) 69.77 Distilled water to make 100 A six milliliter quantity of the above composition was found to be very effective as a laxative when packaged in a small plastic disposable unit.

An important characteristic of the compositions of this invention is that they function as effective laxatives when administered in only a very small quantity (e.g. 2-20-ml. and preferably 510 ml.), whereas the laxative products available on the market prior to this invention have had to employ much greater quantities in order to obtain the desired result. The fact that the compositions of this invention function as effective laxatives in small dosages of only 2-20 ml. is believed to be convincing evidence that the particular combination of ingredients employed produces an unexpected result. However, whereas the claims which follow make mention of a highly effective and useful dosage range, there is no intention that the claims should be restricted thereto because the invention is believed to reside in the discovery of the particular combination of ingredients which makes the use of very small dosages possible.

The laxative compositions prepared in accordance with the above examples were found to completely remove colonic contents without requiring large quantities of water to be introduced into the colon and without disturbing the fluid balance of the body.

Whenever the expression consisting essentially of is used in the attached claims it is intended to refer to the components which are essential to the composition, namely an alkali salt of an aliphatic polybasic hydroxy acid selected from the group consisting of citric acid, malic acid, tartaric acid and ascorbic acid and a polyhydric alcohol having at least 5 hydroxyl groups, and the expression does not exclude other components from the composition which do not render it unsuitable as a laxative or enema, such as Wetting agents, water, glycerol, viscosity increasing agents, pH stabilizers, anaesthetics, etc.

Those skilled in the chemical arts, and particularly in the art to which this invention pertains, will readily appreciate that many modifications of the basic invention set forth here are possible. For example, it would not involve invention to try closely related compounds in view of the present broad disclosure or in trying amounts different than those disclosed. All such obvious modifications would not avoid infringement under the well known doctrine of equivalents.

What is claimed is:

1. A composition which is highly effective as a laxative when administered in volumes of only 2-20 ml., consisting essentially of the following ingredients:

(a) an alkali salt of an aliphatic polybasic hydroxy acid selected from the group consisting of citric acid, malic acid, tartaric acid and ascorbic acid-2 to 15%,

(b) an alcohol selected from the group consisting of manitol, sorbitol, dulcitol, arabitol, xylitol and adonitoll0 to (c) water--5 to 70%.

2. A highly effective therapeutically acceptable laxative composition as set forth in claim 1, containing in addition glycerol.

3. A highly effective therapeutically acceptable laxative composition as set forth in claim 1, containing in addition a wetting agent.

4. A highly effective therapeutically acceptable laxative composition, as set forth in claim 1 wherein the alcohol is sorbitol.

5. A highly eifective therapeutically acceptable laxative composition, as set forth in claim 1 wherein the said alkali salt is sodium citrate.

6. A composition which is highly efiective as a laxative when administered in a volume of about 6 milliliters, consisting essentially of:

Percent Sodium lauryl sulfoacetate (64.8% by weight)..- 1.09 Sorbic acid .078

Glycerol 9.77

Sodium citrate 7.03

References Cited by the Examiner Jordan-Modern Drug Encyclopedia, 7th ed., February 1958, pages 1033 and 1181, Drug Publications Inc., New York.

JULIAN S. LEVITT, Primary Examiner.

FRANK CACCIAPAGLIA, JR., Examiner. 

1. A COMPOSITION WHICH IS HIGHLY EFFECTIVE AS A LAXATIVE WHEN ADMINISTERED IN VOLUMES OF ONLY 2-20 ML., CONSISTING ESSENTIALLY OF THE FOLLOWING INGREDIENTS: (A) AN ALKALI SALT OF AN ALIPHATIC POLYBASIC HYDROXY ACID SELECTED FROM THE GROUP CONSISTING OF CITRIC ACID, MALIC ACID, TARTARIC ACID AND ASCORBIC ACID -2 TO 15%, (B) AN ALCOHOL SELECTED FROM THE GROUP CONSISTING OF MANITOL, SORBITOL, DULCITOL, ARABITOL, XYLITOL AND ADONITOL - 10 TO 80%, (C) WATER - 5 TO 70%. 